RapaCaspase-9-based suicide gene applied to the safety of IL-1RAP CAR-T cells.
Journal
Gene therapy
ISSN: 1476-5462
Titre abrégé: Gene Ther
Pays: England
ID NLM: 9421525
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
07
11
2022
accepted:
18
04
2023
revised:
30
03
2023
medline:
20
9
2023
pubmed:
13
5
2023
entrez:
12
5
2023
Statut:
ppublish
Résumé
Even if adoptive cell transfer (ACT) has already shown great clinical efficiency in different types of disease, such as cancer, some adverse events consistently occur, and suicide genes are an interesting system to manage these events. Our team developed a new medical drug candidate, a chimeric antigen receptor (CAR) targeting interleukin-1 receptor accessory protein (IL-1RAP), which needs to be evaluated in clinical trials with a clinically applicable suicide gene system. To prevent side effects and ensure the safety of our candidate, we devised two constructs carrying an inducible suicide gene, RapaCasp9-G or RapaCasp9-A, containing a single-nucleotide polymorphism (rs1052576) affecting the efficiency of endogenous caspase 9. These suicide genes are activated by rapamycin and based on the fusion of human caspase 9 with a modified human FK-binding protein, allowing conditional dimerization. RapaCasp9-G- and RapaCasp9-A-expressing gene-modified T cells (GMTCs) were produced from healthy donors (HDs) and acute myeloid leukemia (AML) donors. The RapaCasp9-G suicide gene demonstrated better efficiency, and we showed its in vitro functionality in different clinically relevant culture conditions. Moreover, as rapamycin is not pharmacologically inert, we also demonstrated its safe use as part of our therapy.
Identifiants
pubmed: 37173386
doi: 10.1038/s41434-023-00404-2
pii: 10.1038/s41434-023-00404-2
pmc: PMC10506905
doi:
Substances chimiques
Caspase 9
EC 3.4.22.-
Interleukin-1 Receptor Accessory Protein
0
Sirolimus
W36ZG6FT64
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
706-713Informations de copyright
© 2023. The Author(s).
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